Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions.

Abstract

Many human genes have adapted to the constant threat of exposure to infectious agents; according to the "hygiene hypothesis," lack of exposure to parasites in modern settings results in immune imbalances, augmenting susceptibility to the development of autoimmune and allergic conditions. Here, by estimating the number of pathogen species/genera in a specific geographic location (pathogen richness) for 52 human populations and analyzing 91 interleukin (IL)/IL receptor genes (IL genes), we show that helminths have been a major selective force on a subset of these genes. A population genetics analysis revealed that five IL genes, including IL7R and IL18RAP, have been a target of balancing selection, a selection process that maintains genetic variability within a population. Previous identification of polymorphisms in some of these loci, and their association with autoimmune conditions, prompted us to investigate the relationship between adaptation and disease. By searching for variants in IL genes identified in genome-wide association studies, we verified that six risk alleles for inflammatory bowel (IBD) or celiac disease are significantly correlated with micropathogen richness. These data support the hygiene hypothesis for IBD and provide a large set of putative targets for susceptibility to helminth infections.

Haplotype genealogy for IL1F5, IL1F7, and IL7R gene regions. The analyzed regions correspond to the largest LD block for each gene (Fig. S2). Each node represents a different haplotype, with the size of the circle proportional to the haplotype frequency. Nucleotide differences between haplotypes are indicated on the branches of the network. Circles are color-coded according to population (gray, AA or YRI; white, EU). The chimpanzee sequence is also shown (black). Fig. S2 is available at http://www.jem.org/cgi/content/full/jem.20082779/DC1.

Estimated trees for IL1F5, IL1F7, and IL7R gene regions. The analyzed regions correspond to the largest LD block for each gene (Fig. S2). Mutations are represented as black dots and named for their physical position along the regions. The absolute frequency of each haplotype is also reported. Fig. S2 is available at http://www.jem.org/cgi/content/full/jem.20082779/DC1.